Investigating the Shared Genetic Architecture Between Psychiatric Disorders and Executive Function.

Background: Evidence for widespread comorbidity of executive dysfunctions with psychiatric disorders suggests common mechanisms underlying their pathophysiology. However, the shared genetic architectures between psychiatric disorders and executive function (EF) remain poorly understood.

Methods: Leveraging large genome-wide association study datasets of European ancestry on bipolar disorder ( = 353,899), major depressive disorder ( = 674,452), and schizophrenia ( = 130,644) from the Psychiatric Genomics Consortium and iPSYCH and a common factor of EF ( = 427,037) from UK Biobank, we systematically investigated the shared genomic architectures between psychiatric disorders and EF with a set of statistical genetic, functional genomic, and gene-level analyses.

Results: Our study demonstrated substantial genetic overlaps and significant genetic correlations between psychiatric disorders and EF. EF showed an estimated 95.9%, 98.1%, and 99.2% of phenotype-influencing variants, as well as 50, 23, and 130 genomic loci shared with bipolar disorder, major depressive disorder, and schizophrenia, respectively. Single nucleotide polymorphism heritability enrichment suggests that the genetic architecture of psychiatric disorders and EF involves the brain's frontal cortex and prefrontal glutamatergic neurons 1 and 2. Functional genomic analysis of shared variants identified 12 functional regulatory variants that regulate gene expression by affecting the binding affinities of 5 transcription factors. In addition, functional characterization analyses of shared genes revealed potential common biological mechanisms related to synaptic processes and fetal brain development.

Conclusions: Our findings provide evidence for extensive shared genetic architectures between psychiatric disorders and EF and have valuable implications for future mechanistic investigations and drug development efforts.